Burtness B, Belker M, Stoltz M, Peccerillo K M, Lamb L A, Chmael S E, McKeon A, Clark M B, Winship J, Marsh J C, Pizzorno G, DeVita V T
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
Cancer J. 2000 Sep-Oct;6(5):309-15.
(E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule.
The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients.
Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred.
(E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.
（E）-2'-氟亚甲基-2'-脱氧胞苷是一种新型抗代谢物。临床前试验已显示其在各种人类肿瘤异种移植模型中具有抗增殖活性，并且还表明频繁给药方案的疗效最佳。我们对晚期癌症患者进行了MDL 101,731静脉输注的I期试验，以确定该药物每周给药两次时的最大耐受剂量和剂量限制性毒性。
该药物每周给药两次，共3周，随后休息2周。初始剂量为16mg/m²。如果出现持续性中性粒细胞减少，则将剂量降至12mg/m²。前六名患者的所有毒性在第一个休息周结束时均得到缓解。随后的四名患者的给药方案改为治疗3周后休息1周。
由于剂量限制性毒性（主要是血液学毒性），超过16mg/m²的剂量递增不可行。未观察到不可逆或危及生命的毒性。还观察到2级非感染性发热、粘膜炎和厌食。在病情稳定的患者中，有一名直肠癌患者接受过大量预处理，其指示性病变在7个月内减少了38%。
（E）-2'-氟亚甲基-2'-脱氧胞苷是一种新型抗代谢物，在接受过大量预处理的患者中具有抗癌活性的证据。该药物每周给药两次时的最大耐受剂量为16mg/m²。
